Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review

Abstract

In recent years, lymphangiogenesis, the process of lymphatic vessel formation from existing lymph vessels, has been demonstrated to have a significant role in diverse pathologies, including cancer metastasis, organ graft rejection, and lymphedema. Our understanding of the mechanisms of lymphangiogenesis has advanced on the heels of studies demonstrating vascular endothelial growth factor C as a central pro-lymphangiogenic regulator and others identifying multiple lymphatic endothelial biomarkers. Despite these breakthroughs and a growing appreciation of the signaling events that govern the lymphangiogenic process, there are no FDA-approved drugs that target lymphangiogenesis. In this review, we reflect on the lessons available from the development of antiangiogenic therapies (26 FDA-approved drugs to date), review current lymphangiogenesis research including nanotechnology in therapeutic drug delivery and imaging, and discuss molecules in the lymphangiogenic pathway that are promising therapeutic targets.

Keywords: angiogenesis; lymphangiogenesis.

Figure I. Trend in FDA approval of anti-angiogenic therapies

In 2004, bevacizumab became the first anti-angiogenic therapy approved for the treatment of metastatic colorectal cancer, and the approval of erlotinib and pegaptanib followed shortly after in the same year. Regorafenib, a treatment for hepatocellular carcinoma, is the most recently approved anti-angiogenic therapy. We observe that from 2008 to 2012 there was a steady increase of the number of FDA-approved drugs. A total of 7 anti-angiogenic drugs were approved by the FDA. This steady increase reflects the growing interest in using anti-angiogenic drugs in cancer treatment. There are 26 molecules approved for anti-angiogenic therapy, some with multiple, unique indications. Drugs were counted once per approved indication (e.g., Afatinib is counted for one approval in 2013 and one approval for a separate indication in 2016.)

Figure II. Number of papers found in PubMed searches for “lymphangiogenesis” per year since 1986

The published literature devoted to lymphangiogenesis research has grown dramatically since 1996, when VEGF-C and -D were discovered to be lymphangiogenic factors. The number of published studies steadily increased from 1997 to 2013 from less than 10 to more than 300. The volume of research on lymphangiogenesis increased by more than 50 times after the discovery of VEGF-C, VEGF-D, and the characterization of three lymphatic vessel biomarkers—LYVE-1, Prox-1, and podoplanin. These events proved to be ground-breaking for research into lymphangiogenesis.

Figure III. Clinical trials of anti-angiogenic chemotherapy and anti-lymphangiogenic chemotherapy

An advanced search of NIH U.S National Library of Medicine ClinicalTrials.gov shows a steady approval rate of clinical trials for anti-angiogenic therapies. In contrast, clinical trials for therapies targeting lymphangiogenesis are sparse. The only observable approvals of anti-lymphangiogenic therapies occurred in 2005 and 2010, with less than 10 approvals in total. While the number of anti-angiogenic chemotherapies approved in 2008 was well beyond 40, the number of anti-lymphangiogenic therapies was far fewer.

Figure IV. Active Phase III clinical trials for anti-angiogenic therapies (as of August, 2017)

Lenalidomide and bevacizumab have been tested in the highest numbers of clinical trials among all anti-angiogenic therapies. Sorafenib has been tested in the most clinical trials for receptor tyrosine kinase inhibitors. Sunitinib and other receptor tyrosine kinase inhibitors account for around 40% of all related clinical trials, while monoclonal antibody (mAb) drugs account for around 42%, of which more than 25% trials tested bevacizumab. The rest of the trials were for immunomodulatory drugs like thalidomide and lenalidomide.

Figure V. Schematic of VEGF pathway target sites of FDA-approved anti-angiogenesis drugs and potential VEGF pathway target sites for future anti-lymphangiogenesis drugs

Axitinib, Bevacizumab, Cabozantinib, Nintedanib, Pazopanib, Pegaptanib, Ramuricumab, Ranibizumab, Regorafenib, Sorafenib, Sunitinib, and Vandetanib are approved anti-angiogenic therapies that target VEGF-mediated angiogenesis. Inhibition of a VEGF ligand, a VEGFR binding site, or VEGFR tyrosine kinase activity leads to a reduction in angiogenesis. This strategy can potentially be translated for lymphangiogenesis-targeted drug design. Development of anti-lymphangiogenic therapies may follow the design of anti-angiogenic therapies by interrupting the lymphangiogenic factor VEGF-C, its receptors VEGFR2 and VEGFR3, or the tyrosine kinase activity of VEGFR2 and VEGFR3. HA, hemangiogenic; LA, lymphangiogenic.

Figure VI. Schematic of EGF pathway target sites of FDA-approved anti-angiogenesis drugs

EGFR (also known as ERBB1 and HER1) and ERBB2 (also known as HER2/neu) are the main therapeutic targets of currently available anti-angiogenic drugs. ERBB2 lacks the ability to bind growth factor ligands and forms heterodimers with EGFR, ERBB3, or ERBB4. Monoclonal antibodies targeting the extracellular domain such as trastuzumab and pertuzumab prevent heterodimer formation, while others such as cetuximab, necitumumab, and panitumumab competitively inhibit EGFR ligand binding. Receptor tyrosine kinase inhibitors target the intracellular kinase domains and prevent signaling downstream of ligand-binding and dimer formation.